Colorectal cancer (CRC) is the fourth most commonly diagnosed malignancy in adults. Although significant progress has been made in early detection, diagnosis and treatment, CRC remains the second leading cause of cancer-related deaths in the U.S. and first after smoking-related deaths are excluded. One factor contributing to successful outcome from CRC is early detection, largely performed by periodic colonoscopy. Recently, there is growing appreciation that cancer morphology at the time of presentation can greatly impact the frequencies of detection. In particular, classical polypoid lesions (polyps) are detected and removed during colonoscopy at a much higher frequency than flat ployps, although there is growing evidence that the latter may have a higher propensity to become invasive at much smaller sizes. Little is known about how or why certain cancer pathologies form or even whether this is a stochastic process or if there are specific genetic or environmental factors contributing to distinct cancer morphologies. Fortuitously, we have discovered novel mouse models of human CRC that consistently and almost exclusively produce flat adenomas compared to the much more frequent polypoid adenoma that occurs in the vast majority of mouse models. These results strongly suggest that there are specific genetic factors that determine CRC morphology. Using these new mouse models, we propose to identify the molecular characteristics that distinguish polypoid from flat CRCs and to identify the genetic factors responsible for determining cancer morphology. Although we will largely rely on a discovery-driven genetic approach to achieve these goals, our underlying hypotheses are that a distinct set of cancer modifiers controls susceptibility to flat CRCs and that there there exists specific host genetic factors that determine the type of CRC morphology an individual will develop. Investigation of this hypothesis will be achieved by 1) molecularly characterizing factors contributing to distinct histopathologies, 2) determining the number and genetic locations of flat adenoma modifiers, and 3) fine mapping and identifying candidate modifiers genes. PUBLIC HEALTH RELEVANCE: The identification genetic factors that are responsible for specific subsets of colorectal cancers offers hope that personalized medicine can be applied to the treatment of colorectal cancer. The proposed studies are aimed at identifying genetic differences among individuals that predispose them to develop flat adenomas, a histologically distinct type of colorectal cancer that is difficult to detect during routine colonoscopy. The identification of genetic polymorphisms predisposing patient to flat adenomas will be useful as prognostic markers for individuals needing extra scrutiny during colonoscopy.